1-cyano-2-imino-3,3-diphenylpyrrolidines

ABSTRACT

NOVEL 2-IMINOPYRROLIDINES SUBSTITUTED IN THE 1-POSITION ARE PREPARED FROM 2-AMINO-$&#39;&#39;-PYRROLINES. THE NOVEL PYRROLIDINES ARE USEFUL AS ANTI-DIABETIC AND HYPOGLYCEMIC AGENTS SINCE THEY EFFECT A LOWERING OF THE BLOOD SUGAR CONTENT IN WARM BLOODED ANIMALS.

United v States Patent C) M 3,772,413 1-CYANO-2-IMINO-3,3-DIPHENYLPYRROLIDINES Hermann Bretschneider, Wilhelm Kliitzer, and Rudolf Franzmair, Innsbruck, Austria, assignors to Holfmann- La Roche Inc., Nutley, NJ. No Drawing. Original application Aug. 1, 1969, Ser. No. 846,916, now Patent No. 3,665,012. Divided and this application Oct. 8, 197'1,Ser. No. 187,839 Claims priority, application Switzerland, Aug. 7, 1968,

l 11,854/68 Int. Cl. C07d 27/04 US. Cl. 260-32662 2 Claims 3 I ABSTRACT OF THE DISCLOSURE Novel Z-iminopyrrolidines substituted in the 1-position are prepared from 2-amino-A-pyrrolines. The novel pyrrolidines are useful as anti-diabetic and hypoglycemic agents since they effect a lowering of the blood sugar content in warm blooded animals.

@ This is adivision of application Ser. No. 846,916, filed Aug. 1, 1969, now US. Pat. No. 3,665,012.

' DESCRIPTION OF THE INVENTION The present invention relates to novel pyrrolidine compounds. More particularly, it relates to pyrrolidine compounds represented by the formula R2 Ra Ra and the corresponding pharmaceutically acceptable acid addition salts.

' As used herein, the term lower alkyl either alone or in combination with another radical denotes straight or branched chain alkyl groups containing from 1 to 7 carbon atoms inclusive, such as methyl, ethyl, propyl, isop'ropyl, butyl, pentyl, hexyl and the like. The term lower --cycloalkyl denotes cycloalkyl groups containing from 4 to 7 carbon atoms inclusive in the ring. Preferred lower cycloalkyls are those which contain 5 or 6 carbon atoms,

such as cyclopentyl and cyclohexyl. The term lower cycloalkyl denotes cycloalkenyl groups containing from 4 to 7 carbon atoms inclusive in the ring. Preferred lower cycloalkenyls are those containing 5 or 6 carbon atoms, such as cyclopentenyl and cyclohexenyl. The term lower alkoxy denotes alkoxy groups containing from 1 to 7 carbon atoms, for example methoxy, ethoxy or propoxy. Typical suitable lower alkoxy-lower alkyl groups are methoxy-methyl, methoxy-ethyl and the like. A typical suitable lower alkyl substituted phenyl group is, for example, tolyLTypical suitable lower alkoxy substituted phenyl groups are, for example, p-methoxy phenyl, p-ethoxy suitable di-lower alkylamino-lower alkyl groups are, for

3,772,413 Patented Nov. 13, 1973 example, dimethylamino and diethylamino-ethyl, -propyl, -butyl and the like. The term halogen as used herein denotes all four halogens, i.e., chlorine, fluorine, bromine, and iodine. A typical suitable halogen substituted phenyl group is, for example, p-chlorophenyl.

A preferred group of compounds falling within the scope of Formula I are those wherein R and R each represent a phenyl group, R and R each represent hydrogen or lower alkyl groups, preferably methyl or ethyl, R and R are hydrogen, and R is hydrogen, lower alkyl, lower alkoxy-lower alkyl, or lower carbalkoxy-lower alkyl. The compounds falling within the scope of this preferred group may be represented by the following formula R7 I-a wherein R and R are hydrogen or lower alkyl, preferably methyl or ethyl, X is oxygen or sulfur, and R is hydrogen, lower alkyl, lower alkoxy-lower alkyl, or lower carbalkoxy-lower alkyl,

wherein R -R are as described above or by reacting an H-tautomer of a compound represented by Formula II with a compound containing the ('TNHR1 group, wherein X and R are as described above.

The H-tautomers of the 2-amino-A'-pyrrolines of Formula II above can be structurally identified as Z-iminopyrrolidines represented by the following formula R R, R, RIJ a -N Rt NE E 1 11-21 wherein R R are as described above.

Examples 'of compounds containing the (II/NHR1 group are: isothiocyanates, such as lower alkyl isothiocyanates, for example, n-butyl isothiocyanate, lower alkoxy-lower alkyl isothiocyanates, for example, me-

-thoxy-methyl isothiocyanate, and lower carbalkoxy-lower alkyl isothiocyanates, for example, carbethoxymethyl isothiocyanate; or isocyanates, such as lower alkyl isocyanates, for example, n-butyl-isocyanate.

The reactions between compounds represented by Formulas II and II-a and the compounds containing the group is conducted at room temperature, e.g., about 20 C. to about 25 C., or if necessary, at a temperature below room temperature. The reaction is carried out in an inert organic solvent such as an aromatic hydrocarbon, for example, benzene, toluene or xylene; an aliphatic hydrocarbon, for example, petroleum ether; an aliphatic alcohol, for example, methanol or ethanol; a chlorinated hydrocarbon, for example chloroform; or an ether, for example, dioxane or tetrahydrofuran. The reaction may also be conducted using dimethylformamide or acetonitrile as the inert solvent.

The compounds represented by Formula II, used as the starting material for the above described process, may be prepared from R R -disubstituted acetonitriles. The appropriately substituted acetonitrile is reacted with an N- carbalkoxy ethyleneimine (which may be lower alkyl or di-lower alkyl substituted) in the presence of a basic condensation agent such as sodamide. The Z-carbalkoxyamino-A'-pyrroline thus obtained is then heated with aqueous alcoholic alkali to obtain the desired 2-amino-A'- pyrroline.

Alternatively, the compounds represented by Formula II may be obtained by the conversion of a Mannich base (prepared by the reaction between a malonic ester of the formula R CH(COO-lower alkyl) formaldehyde and dimethylamine) into the iodomethylate. The thus obtained iodomethylate is then condensed with an R R disubstituted acetonitrile in the presence of sodium ethylate. Saponification of the condensation product with alkali hydroxide gives a carboxylic acid which is transformed into the acid chloride with thionyl chloride. The acid chloride is subjected to Curtis degradation to yield an isocyanate represented by the formula R1 R3 NC+CHz-CHNCO which can be saponified to the amine in methanol with alkali hydroxide.

Following a second possible method of preparing compounds represented by Formulas I and La, a compound represented by the formula R, R5 R3 NCC-C-CNC s 1'1. ll. Ih wherein R -R are as described above is reacted with an amine represented by the formula Rq-NH wherein R7 is as described above,

to yield the desired Z-iminopyrrolidines.

The reaction between compounds represented by Formulas III and IV is carried out at room temperature e.g. about C. to about C., or if necessary, below room temperature. The reaction is carried out in an inert organic solvent such as an aromatic hydrocarbon, for example, benzene, toluene or xylene; an aliphatic hydrocarbin, for example, petroleum ether; an aliphatic alcohol, for example, methanol or ethanol; a chlorinated hydro carbon, for example, chloroform; or an ether, for example, dioxane or tetrahydrofuran. The reaction may also be conducted using dimethylformamide or acetonitrile as the inert solvent.

The compounds represented by Formula III can be obtained by treating compounds represented by Formula II with thiophosgene. Alternatively, a correspondingly substituted S-cyanopropyl isocyanate (prepared as described above in the preparation of co pounds repres y (III) R1 R9 R4 wherein R -R are as described above is treated with an appropriate base to yield the desired Z-iminopyrrolidines. This cyclization reaction is conducted at room temperature, e.g., about 20 C. to about 25 C. For the purposes of the reaction, the base employed to effect the cyclization of compounds represented by Formula V is selected from the group consisting of alkali metal alcoholates, such as, for example, sodium or potassium methylate or ethylate; or alcoholic caustic potash. The compounds represented by Formula V may be prepared by the reaction of a correspondingly substituted B-cyanopropyl isocyanate with a compound represented by Formula IV.

In yet another possible method of preparing compounds represented by Formulas I and La, a compound represented by 'Formula II is reacted with a cyanogen halide, preferably cyanogen bromide, at room temperature e.g., about 20 C. to about 25 C., or, if necessary, below room temperature. The reaction is carried out in the presence of a hydrogen halide binding agent, for example, an alkali hydroxide or carbonate. Two isomeric reaction products can form as a result of this reaction, depending in each case on whether the cyano group is added to the ring N-atom (N or to the amino group in the 2-position (N The isomers may be separated on the basis of their differing solubility in dilute hydrochloric acid, since only the N -isomer is soluble in the acid. The N -cyano derivative, which is represented by the formula wherein R -R are as described above can be hydrated to the ureido compounds represented by Formula I (X=O) by treatment with an appropriate acid, preferably alcoholic or aqueous hydrochloric acid. The N -cyano derivatives represented by Formula VI may also be converted into the thioureido compounds represented by Formula I (X=S) by treatment with hydrogen sulphide or a thiophosphoric acid ester such as a thiophosphoric acid 0,0-dialkyl ester. I

The compounds represented by Formula I exhibita high level of hypoglycemic activity, evidencing their usefulness as antidiabetics. The hypoglycemic activity of the compounds represented by Formula I is shown in warm blooded animals utilizing a standard blood glucose content test. In this test, groups of 5 rats weighing from about 60 to g. are used. Oral application of a suspension of the compound in polyethylene glycol (Carbowax 400) is performed by stomach tube. Control rats are given the vehicle alone. At intervals of 1, 3 and 16 hours after administration of the compound, blood is obtained from the test animals by decapitation and the blood is immediately deproteinized [Somogyi, M., J. Biol. Chem., 160, 69-73 (1945)]. Glucose content in the blood is determined by the Techm'can Auto-Analyzer using the enzymatic glucose oxidase-peroxidase-tolidine procedure [Watson, D., Anal. Biochem., 3, 131 (1962)]. The results from five rats are averaged at each time interval and are reported as percent deviation from control. Results are expressed as percent deviation in the blood glucose value from the control pretreatment value.

If the l, 3 or 16 hour average is greater than the control, the result is a positive percentage. If the control average is higher, the result is a negative percentage. The significance of the results is calculated by a computer program. Results are expressed as percent deviation from control [numerical value preceded by (-l-) or Following the test procedure discussed above, the compounds of Formula I are shown to possess hypoglycemic activity which makes them useful as anti-diabetic agents. Following this standard test procedure, compounds such as those listed below show deviations evidencing hypoglycemic activity at the indicated dosage levels:

The compound l-(N-methoxymethyl)-thiocarbamoyl-2- imino-3,3-diphenyl-S-methylpyrrolidine when administered at the rate of 353 mg./kg. gave 0, 10, and -21 percent when tested as above.

The compound 1-(N-n-butylthiocarbamoyl)-2-imino- 3,3-diphenyl-S-methylpyrrolidine when administered at a rate of 366 nag/kg. gave -7, 12, and -17 percent when tested as above.

The compound 1- (N-3'-dimethylaminopropyl)-thiocarbamoyl-2-imino-3,3-diphenylpyrrolidine when administered at a rate of 118 mg./kg. gave +2, -5, and 23 percent when tested as above.

The compound l-(N-n-butylcarbamoyl)-2-imino-3,3- diphenyl-S-methylpyrrolidine when administered at a rate of 350 mg./kg. gave +5, 1, and --17 percent when tested as above.

The compounds represented by Formula I may be incorporated into pharmaceutical formulations according to conventional techniques so that the drug will be present in the formulation in an amount from about 100 to about 600 mg., preferably in anamount from about 300 to about 600 mg., compounded into conventional pharmaceutical dosage forms which contain the active ingredients or their pharmaceutically acceptable salts in admixture 'with a pharmaceutically suitable organic or inorganic inert carrier material. Representative of such inert carrier materials are water, gelatin, lactose, starches, magnesium stearate, talc, etc. The pharmaceutical dosage formulations can be compounded as tablets, dragees, capsules and the like. They may also contain other therapeutically pharmacologically active substances.

The following examples are illustrative but not limitative of the invention. Temperatures, unless otherwise stated, are expressed in degrees centigrade.

EXAMPLE 1 0.01 mol of 2-amino-3,3-diphenyl-5-rnethyl-A -pyrroline are dissolved in 20 ml. of ethanol at room temperature. The solution is treated with 0.01 mol of methoxymethyl isothiocyanate and allowed to stand for 4 hours. The precipitate is filtered off, washed with a little cold ethanol and dried. l-(N-methoxymethyl)-thiacorbamoyl- 2-imino-3,3-diphenyl-S-methyl-pyrrolidine, melting point 101, is obtained.

EXAMPLE 2 From 2-amino-3,3-diphenyl-5-methyl-A -pyrroline and n-butyl isothiocyanate there is obtained l-(N-n-butyl)- thiocarbamoyl-2-imino-3,3-diphenyl 5 methylpyrrolidine, melting point From 2-amino-3,3-diphenyl-5-methyl-A -pyrroline and dimethylaminopropyl isothiocyanate there is obtained 1- (N-3'-dimethylaminopropyl)-thiocarbamoyl 2 imino- 3,3-diphenyl-S-methylpyrrolidine, melting point From 2-amino-3,3-diphenyl-A -pyrroline and dimethylaminopropyl isothiocyanate there is obtained 1-(N-3'-dimethylaminopropyl)-thiocarbamoyl 2 imino 3,3 diphenylpyrrolidine of melting point 83-84".

EXAMPLE 3 0.01 mol of 2-amino-3,3-diphenyl-5-methyl-A -pyrroline are suspended in 20 ml. of cold absolute benzene. 0.991 g. of n-butyl isocyanate are thereafter added. The reaction mixture is shaken up to solution and allowed to stand at room temperature for 1 hour. The benzene is then taken off in vacuum at 25 bath-temperature and the oily residue treated with a mixture of 10 ml. of ethanol, 10 ml. of water and 2 ml. of 10% acetic acid. Crystalline 1 (N-n-butylcarbamoyl)-2-imino-3,3-diphenyl-5- methylpyrrolidine, melting point 8082 (from aqueous methanol) is obtained.

EXAMPLE 4 In a similar fashion as disclosed in Example 3, from 2- amino-3,3-diphenyl-A -pyrroline there is obtained l-(N-nbutylcarbamoyl)-2-imino-3,3 diphenylpyrroline, melting point 74 (from petroleum ether).

EXAMPLE 5 0.73 g. of n-butylamine are slowly added to 2.76 g. of 2,2-diphenyl-4-isocyanatovaleronitrile in 20 ml. of benzene. The reaction mixture is allowed to stand at room temperature for 1 hour and then the solvent is removed in vacuum. The oily residue (3.26 g.) is triturated with a little ether, whereby N-n-butyl-N'-(1-methyl-3,3-diphenyl- 3-cyanopropyl)-urea crystallizes, melting point 8991 (from ethanol Water).

EXAMPLE 6 3 drops of 1.3 mol sodium methylate solution are addai to 0.5 g. of N-n-butyl-(1-methyl-3,3-diphenyl-3-cyanopropyl)-urea in 10 ml. of methanol. The reaction mixture is allowed to stand at room temperature for 60 hours, thereafter diluted with 5 ml. of water and cooled to 0, whereby 1 (N-n-butylcarbamoyl)-2-imino-3,3-diphenyl- S-methylpyrrolidine crystallizes.

EXAMPLE 7 To 5 g. of 2-amin0-3,3-diphenyl-S-methyl-N-pyrroline in 120 ml. of benzene there are added dropwise, with ice-cooling, 1.15 g. of thiophosgene dissolved in 25 ml. of benzene. The reaction mixture is stirred at room temperature for 4 hours, the precipitate separated off and the solution shaken 10 minutes with 100 ml. of 5% sodium bicarbonate solution. The organic phase is washed with water and dried over sodium sulphate. After evaporation of the solvent, the residue is distilled at 0.01 torr and bath-temperature. The distillate, 2,2-diphenyl-4-isothiocyanatovaleronitrile, crystallizes on trituration with methanol, melting point 93 (from methanol).

' EXAMPLE 8 1.21.3 equivalents of n-butylamine are added to 0.5 g. of 2,2 diphenyl 4 isothiocyanatovaleronitrile in 15 ml. of ethanol. The reaction mixture is allowed to stand at room temperature for three hours and then concentrated under reduced pressure. The residue is triturated with a little ethanol and yields 0.52 g. of crystalline 1- (N n butylthiocarbamoyl) 2 imino 3,3 diphenyl- S-methylpyrrolidine.

7 EXAMPLE 9 A solution of 16 g. of 2 amino 3,3 diphenyl methyl A pyrroline in 130 ml. of chloroform is treated with a solution of g. of anhydrous potassium carbonate in ml. of water. The solution is vigorously stirred at 10-15 for 3 /2 hours with a solution of 10 g. of cyanogen bromide in ml. of chloroform. After an additional 4 hours, the chloroform phase is separated off and repeatedly shaken out with half-concentrated hydrochloric acid. The hydrochloric acid extracts are alkalized, with cooling, with potassium carbonate solution, yielding 1 cyano 2 imino 3,3 diphenyl 5 methylpyrrolidine, melting point 145.

EXAMPLE 10 1.3 g. of l-cyano 2 imino 3,3 diphenyl 5 methylpyrrolidine are suspended in 30 ml. of absolute ether and treated dropwise with stirring at 0 with a solution of 0.89 g. of dithiophosphoric acid 0,0-diethyl ester in 5 ml. of ether. The reaction mixture is stirred at 0 for an hour, thereafter saturated with dry hydrogen chloride forming a clear solution. The solvent is evaporated oif under vacuum and the residue dissolved in ml. of water. The aqueous solution is washed with ether, cooled and made alkaline with Z-N NaOH, yielding l-thjocarbamoyl 2 imino 3,3 diphenyl 5 methylpyrrolidine, melting point (from ethanol).

What is claimed is: 1. A compound of the formula wherein R and R are individually hydrogen or lower alkyl and the pharmaceutically acceptable acid addition salts thereof.

2. The compound of claim 1 wherein R is hydrogen, and R is methyl, i.e. 1-cyano2-imino-3,3-diphenyl-5- methylpyrrolidine.

References Cited UNITED STATES PATENTS 5/1964 Bortnick et a1. 260326.62 X

IIN

JOSEPH A. NARCAVAGE, Primary Examiner 

